ROLE OF CYTOKINES IN GVL (ESB LYMPHOMA) AND GVHD AFTER ADOPTIVE TRANSFER OF ALLOGENEIC T-LYMPHOCYTES IN MICE

ESb lymphoma cells injected i,v, into DBA/2 (H-2(d)) mice multiply rap idly in the liver and kill ail mice in a few days. Adoptive transfer o f allogeneic C57Bl/6 (H-2(b)) tumor-immune or normal splenic lymphocyt es to sublethally irradiated DBA/2 mice induced a marked antitumor sta te, graft-versus-leukemia (GVL), increasing the mean survival time 2-3 -fold, but also induced an acute and lethal graft-versus host disease (GVHD), We have undertaken experiments to try to dissociate GVL from G VHD. Transfer of immune spleen cells induced a greater GVL than transf er of normal spleen cells with an equivalent to GVHD, Three to five mi llion immune or normal CD8(+) T lymphocytes were sufficient to induce both GVL and GVHD. Individual DBA/2 mice were labeled and followed. In mice undergoing GVHD, the spleens were repopulated by donor (H-2(b)) lymphocytes, and tumor necrosis factor-alpha (TNF-alpha) and interleuk in-6 (IL-6) were present in the sera of 26 of 27 and 18 of 20 mice, re spectively, together with increased amounts of TNF-alpha and IL-6 mRNA in their spleens. This was in contrast to DBA/2 mice receiving alloge neic cells but not developing GVHD, Both interferon-alpha/beta (IFN-al pha/beta) and IL-12, which had proven very effective in association wi th adoptive transfer of syngeneic immune T lymphocytes in inhibiting E Sb metastases, enhanced GVHD when administered with allogeneic immune or normal spleen cells, and >90% of mice died. Intensive IL-2 treatmen t inhibited GVHD while maintaining GVL.